Antimalarial activity of primaquine operates via a two-step biochemical relay

Camarda, Grazia, Jirawatcharadech, Piyaporn, Priestley, Richard S, Saif, Ahmed, March, Sandra, Wong, Michael HL, Leung, Suet, Miller, Alex B, Baker, David A, Alano, Pietro
et al (show 5 more authors) (2019) Antimalarial activity of primaquine operates via a two-step biochemical relay. NATURE COMMUNICATIONS, 10 (1). 3226-.

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Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum. The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H<sub>2</sub>O<sub>2</sub>, leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.

Item Type: Article
Uncontrolled Keywords: Liver, Bone Marrow, Humans, Plasmodium falciparum, Malaria, Falciparum, Hydrogen Peroxide, Aminoquinolines, Primaquine, NADP, Cytochrome P-450 Enzyme System, Cytochrome P-450 CYP2D6, Antimalarials, Pharmacokinetics, Dose-Response Relationship, Drug
Depositing User: Symplectic Admin
Date Deposited: 14 Aug 2019 07:46
Last Modified: 19 Jan 2023 00:31
DOI: 10.1038/s41467-019-11239-0
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